Introduction

There are gradients of health when groups of people are classified according to their socioeconomic status, which reflect both income and level of education. The poor suffer earlier mortality and worse health, on the average, than the middle class, which, in turn, is not as healthy as those who are wealthier and/or better educated. Attempts to explain these gradients on the basis of access to health care or such behaviors as smoking have failed to explain the gradient (1;2). Instead there is a need to understand more comprehensively how various aspects of life impact collectively on health, involving such factors as living environment, work, relationships, community, knowledge and practice of health promoting or health damaging behaviors including diet and exercise. In order to do this we must move from groups to individuals and understand how behavior and biology interact.

Often, we use the word "stress" to refer to these biological factors, but this is an oversimplification because they are more that "stress" and include many aspects of lifestyle and daily experience and behavior, including the adjustments to the circadian light-dark cycle. Moreover, the widespread use of the term "stress" in popular culture has made this word a very ambiguous term to describe the ways in which the body copes with psychosocial, environmental and physical challenges. Thus we have been in search of a more comprehensive term for the role of biological mediators in adaptation and maladaptation of the individual to the circumstances of life.

Where Stress Fits In

The body responds to the external and internal environment by producing hormonal and neurotransmitter mediators that set in motion physiological responses of cells and tissues throughout the body, leading to a coordination of physiological responses to the current circumstances. The measurement of the physiological responses of the body to environmental challenges constitutes the primary means of connecting experience with resilience or the risk for disease. Because the subjective experience of stress does not always correlate with the output of physiological mediators of stress(13), the measurement of the physiological responses of the body to environmental challenges constitutes the primary means of connecting experience with resilience or the risk for disease. The so-called "stress mediators," hormones such as cortisol and catecholamines, also vary in their basal secretion according to a diurnal rhythm that is coordinated by the light-dark cycle and sleep-waking patterns, a fact that reinforces the inadequacy of the popular use of the term "stress" as a useful descriptor of the source of all biological dysregulations. For example, the internal biological clock of the hypothalamic suprachiasmatic nucleus regulates cyclicity of sleep and waking and the production of adrenocortical hormones that are entrained by the light-dark cycle; shifting the light-dark cycle, as by trans-Atlantic jet airplane travel, results in dysregulation of adrenocortical hormone and contributes to disruption of sleep, activity, appetite and cognitive function.

With regard to stress, the sudden occurrence of danger, as for a gazelle being chased by a lion or a person confronted by a threat to physical safety, calls forth release of both adrenalin and adrenocortical hormones ("fight of flight" response) that help the body survive the immediate crisis. Indeed, new research has reinforced the fact that the so-called "stress mediators" have protective and adaptive as well as damaging effects, and the search for biological mechanisms that determine protective versus damaging effects of these mediators is a theme in biobehavioral research (22). This search has also led to a new formulation of the relationship between environmental challenge and biological responses.

Allostasis and Allostatic Load

Rather than referring to everything dealing with responses to environmental and psychosocial situations as "stress," we have provided a new formulation using two new terms, "allostasis" and "allostatic load." Allostasis, meaning literally "maintaining stability (or homeostasis) through change" was introduced by Sterling and Eyer (33) to describe how the cardiovascular system adjusts to resting and active states of the body. This notion can be applied to other physiological mediators, such as the secretion of cortisol as well as catecholamines, and the concept of "allostatic load" was proposed to refer to the wear and tear that the body experiences due to repeated cycles of allostasis as well as the inefficient turning-on or shutting off of these responses (22;26). As an example of allostatic load, the persistent activation of blood pressure in dominant male cynomologus monkeys vying for position in an unstable dominance hierarchy is reported to accelerate atherosclerotic plaque formation (17). Blood pressure surges accompany the social confrontations and catecholamines are elevated during those surges. Together, the blood pressure and catecholamine elevations accelerate atherosclerosis, as shown by the fact that the acceleration of atherosclerosis in dominant monkeys was prevented by beta adrenergic blocking drugs (18).

The concept of allostasis and allostatic load envisions a cascade of cause and effect that begins with primary stress mediators, such as catecholamines and cortisol, and leading to primary effects and then to secondary and tertiary outcomes, as will be described below. In order to begin to understand this formulation, Figure 1 summarizes four key features of the model.

Figure 1. The Stress Response and Development of Allostatic Load
Perception of stress is influenced by one's experiences, genetics, and behavior. When the brain perceives an experience as stressful,
physiologic and behavioral responses are initiated leading to allostasis and adaptation. Over time, allostatic load can accumulate,
and the overexposure to neural, endocrine, and immune stress mediators can have adverse effects on various organ systems, leading to
disease. Reprinted from McEwen (22) by permission from the New England Journal of Medicine. Copyright 1998 Massachusetts Medical
Society. All rights reserved.

First, the brain is the integrative center for coordinating the behavioral and neuroendocrine responses (hormonal, autonomic) to challenges, some of which qualify as "stressful" but others of which are related to the diurnal rhythm and its ability to coordinate waking and sleeping functions with the environment. Second, there are considerable individual differences in coping with challenges, based upon interacting genetic, developmental and experiential factors. There is a cascading effect of genetic predisposition and early developmental events, such as abuse and neglect or other forms of early life stress, to predispose the organism to over-react physiologically and behaviorally to events throughout life. Third, inherent within the neuroendocrine and behavioral responses to challenge is the capacity to adapt (allostasis, meaning to achieve stability, or homeostasis, through change); and, indeed, the neuroendocrine responses are set up to be protective in the short-run. For the neuroendocrine system, turning on and turning off responses efficiently is vital (see Figure 2); inefficiency in allostasis leads to cumulative effects over long time intervals, as will be describe below.

Fourth, allostasis has a price (allostatic load, referring to cumulative negative effects, or the price the body pays for being forced to adapt to various psychosocial challenges and adverse environments) that is related to how inefficient the response is, or how many challenges an individual experiences (ie, a lot of stressful events). Thus allostatic load is more than "chronic stress" and encompasses many aspects of an individual's life that affect the regulation and level of the mediators of allostasis. Among the many factors that contribute to allostatic load are genes and early development, as well as learned behaviors reflecting life style choices of diet, exercise, smoking and drinking. All of these factors influence the reactivity of the systems that produce the physiological stress mediators. Thus allostatic load reflects, in part, genetically- or developmentally-programmed inefficiency in handling the normal challenges of daily life related to the sleep-wake cycle and other daily experiences, as well as the adverse physiological consequences of a fat-rich diet, drinking or smoking.

Figure 2. Allostasis in the Autonomic Nervous System and the Hypothalamic- pituitary-adrenal Axis

Allostatic systems respond to stress (upper panel) by initiating the adaptive response, sustaining it until the stress ceases, and then shutting it off (recovery). Allostatic responses are initiated (lower panel) by an increase in circulating catecholamines from the autonomic nervous system and glucocorticoids from the adrenal cortex. This sets into motion adaptive processes that alter the structure and function of a variety of cells and tissues. These processes are initiated via intracellular receptors for steroid hormones, plasma membrane receptors, and second messenger systems for catecholamines. Cross-talk between catecholamines and glucocorticoid receptor signaling systems can occur (see text). Reprinted from McEwen (22) by permission from the New England Journal of Medicine. Copyright 1998 Massachusetts Medical Society. All rights reserved.

Many of the same considerations apply to behavioral, as opposed to physiological, responses to challenge, and there are also protective and damaging aspects to one's behavior. Individuals can act to increase or decrease further risk for harm or disease - for example, antisocial responses such as hostility and aggression vs. cooperation and conciliation; risk taking behaviors such as smoking, drinking, and physical risk-taking vs. self protection; poor diet and health practices vs. good diet, exercise, etc. The linkage of "allostasis" and "allostatic load" probably applies to behavioral responses as well to physiological responses to challenge in so far as the behavioral response, such as smoking or alcohol consumption, may have at least perceived adaptive benefits in the short run but produce damaging effects in the long run.

Allostatic Load Requires Understanding of Physiological Mechanisms

Although allostasis and allostatic load are general concepts to be applied across physiological and behavioral responses, they require in each case an understanding of underlying mechanisms in each system of the body. This understanding begins with the mediators that produce organ- and tissue-specific effects by acting via receptors that are common throughout the body (see Figure 2). The mediators of allostasis include adrenal steroids and catecholamines, primarily, but also other hormones like DHEA, prolactin, growth hormones and the cytokines related to the immune system, as well as local tissue mediators like the excitatory amino acids. In Figure 2, the actions of two mediators, the glucocorticoids and the catecholamines, are shown, acting via receptors that trigger changes throught out the target cell in processes, including both rapid effects and changes in gene expression that have long-lasting consequences for cell function. Thus, whenever a hormone is secreted, there are to be considered both the short-term and long-term consequences of hormone action on cell function.

For each system of the body, there are both short-term adaptive actions (allostasis) that are protective and long-term effects that can be damaging (allostatic load). For the cardiovascular system, a prominent example of allostasis is the role of catecholamines in promoting adaptation by adjusting heart rate and blood pressure to sleeping, waking, physical exertion (33). Yet, repeated surges of blood pressure in the face of job stress or the failure to shut off blood pressure surges efficiently accelerates atherosclerosis and synergizes with metabolic hormones to produce Type II diabetes, and this constitutes a type of allostatic load (see (22)). Closely related to this is the role of adrenal steroids in metabolism. Whereas adrenal steroids promote allostasis by enhancing food intake and facilitating the replenishment of energy reserves, the overactivity of this system involving repeated HPA activity in stress or elevated evening cortisol leads to allostatic load in terms of insulin resistance, accelerating progression towards Type II diabetes, including abdominal obesity, atherosclerosis, and hypertension (4;5).
In the brain, actions of adrenal steroids and catecholamines that are related to allostasis include promoting retention of memories of emotionally-charged events, both positive and negative. Yet, overactivity of the HPA axis together with overactivity of the excitatory amino acid neurotransmitters promotes a form of allostatic load, consisting of cognitive dysfunction by a variety of mechanisms that involve reduced neuronal excitability, neuronal atrophy and, in extreme cases, death of brain cells, particularly in the hippocampus (21;23).

For the immune system, adrenal steroids promote allostasis together with catecholamines by promoting "trafficking," ie., movement, of immune cells to organs and tissues where they are needed to fight an infection or other challenge, and they also modulate the expression of the hormones of the immune systems, the cytokines and chemokines (24). With chronic overactivity of these same mediators, allostatic load results, consisting of immunosuppressive affects when these mediators are secreted chronically or not shut off properly (24). Yet, some optimal levels of these mediators is required to maintain a functional balance within the competing forces of the immune system, and the absence of sufficient levels of glucocorticoids and catecholamines allows other immune mediators to over-react and increases the risk of autoimmune and inflammatory disorders (34). Therefore, an inadequate response of the HPA axis and autonomic nervous system is another type of allostatic load, in which the dysregulation of other mediators, normally contained by cortisol and catecholamines, is a primary factor in a disorder.

Thus, allostatic load may be subdivided into at least 4 subtypes, as summarized in Figure 3.

Figure 3. Four Types of Allostatic Load
The top panel illustrates the normal allostatic response, in which a response is initiated by a stressor, sustained for an appropriate interval, and then turned off. The remaining panels illustrate four conditions that lead to allostatic load: 1) Repeated "hits" from multiple novel stressors; 2) Lack of adaptation; 3) Prolonged response due to delayed shut down; and 4) inadequate response that leads to compensatory hyperactivity of other mediators: e.g., inadequate secretion of glucocorticoid, resulting in increased levels of cytokines that are normally counter-regulated by glucocorticoids). Figure drawn by Dr. Firdaus Dhabhar, Rockefeller University. Reprinted from McEwen (22) by permission from the New England Journal of Medicine. Copyright 1998 Massachusetts Medical Society. All rights reserved.

The first type is simply too much "stress" in the form of repeated, novel events that cause repeated elevations of stress mediators over long periods of time. For example, the amount and frequency of economic hardship predicts decline of physical and mental functioning as well as increased mortality (16). Yet not all types of allostatic load deal with chronic stress. A second type of allostatic load depicted in Fig. 3 involves a failure to habituate or adapt to the same stressor. This leads to the over-exposure to stress mediators because of the failure of the body to dampen or eliminate the hormonal stress response to a repeated event. An example of this is the finding that repeated public speaking challenges, in which most individuals habituated their cortisol response, led a significant minority of individuals to fail to habituate and continue to show cortisol response (14).

A third and related type of allostatic load, also depicted in Fig. 3, involves the failure to shut off either the hormonal stress response or to display the normal trough of the diurnal cortisol pattern. One example of this is blood pressure elevations in work-related stress which turn off slowly in some individuals with a family history of hypertension (11). Another example of perturbing the normal diurnal rhythm is that of sleep deprivation leading to elevated evening cortisol and hyperglycemia within 5d (36) and depressive illness leading to chronically elevated cortisol and loss of bone mineral mass (27).

The fourth type of allostatic load depicted in Figure 3 involves an inadequate hormonal stress response which allows other systems, such as the inflammatory cytokines, to become overactive. The Lewis rat is an example of an animal strain in which increased susceptibility to inflammatory and autoimmune disturbances is related to inadequate levels of cortisol (34;35).

Validation of Allostatic Load

Assessment of allostatic load would optimally incorporate information on "resting" or "usual" levels of allostatic mediators for each individual, as well as assessments of system dynamics (i.e., alterations in the "operating range" of the system parameters in response to stimulation, so as to tap into the 4 types of allostatic load depicted in Figure 3); and it would include information for parameters of all major physiological regulatory systems. Such a goal is rather ambitious, but a first step was made in that direction using available data from the MacArthur Successful Aging Study. Using this data, we previously reported on an initial operational measure of allostatic load which reflects information on levels of physiologic activity across a range of important regulatory systems, including the hypothalamic-pituitary-adrenal and sympathetic nervous systems as well as the cardiovascular system and metabolic processes (32). Our measure of allostatic load reflects only one of the two aspects of physiologic activity postulated to contribute to allostatic load, namely, higher, chronic, steady state levels of activity related to the diurnal variation as well as any residual activity reflecting chronic stress or failure to shut-off responses to acute stressors. Specifically, available data on physiologic activity represent single measures of activity levels rather than assessments of the dynamics of these systems in response to challenge.

Available data from the MacArthur Study provided information on the following parameters (32):

Our initial measure of allostatic load was created by summing across indices of subjects' status with respect to these ten components of allostatic load. For each of the ten indicators, subjects were classified into quartiles based on the distribution of scores in the high function cohort (see (32)). The decision to use distributions in the high function cohort was based on the fact that analyses of relationships between allostatic load and health outcomes were based on longitudinal data for this latter group. Allostatic load was measured by summing the number of parameters for which the subject fell into the "highest" risk quartile (i.e., top quartile for all parameters except HDL cholesterol and DHEA-S for which membership in the lowest quartile corresponds to highest risk).

Several alternative criteria for calculating allostatic load were also examined. One such alternative using a stricter criterion was based on a sum of the number of parameters for which the subject fell into the top (or bottom) 10% of the distribution (i.e., the group at highest "risk"). Another measure of allostatic load was based on averaging z-scores for each of the parameters. In each case, analyses yielded essentially the same results as the measure based on the quartile criteria, though the latter showed the strongest effects. These concurrent results suggest to us that the disease risks associated with allostatic load derive (as the original conceptualization would argue) from being relatively higher on various measures of physiologic regulation rather than only at the most extreme levels. At the same time, simply averaging levels of activity across systems may tend to obscure the impact of elevations in a subset of systems that contribute to higher allostatic load. Thus, we selected an algorithm for allostatic load that avoids the problem of averaging, using instead a count of the number of parameters for which subjects exhibited relatively elevated levels. The 10 components were equally weighted since, based on factor analysis, indicators from physiologic systems defined different factors, and the component loadings on the relevant factors were virtually the same. This measure of allostatic load was then examined for its ability to predict health outcomes over a 2.5 year follow-up. Higher baseline allostatic load scores were found to predict significantly increased risks for incident cardiovascular disease as well as increased risks for decline in physical and cognitive functioning and for mortality (32).

Further Refinement of Allostatic Load

One of the problems with the original conceptualization of allostatic load and its measurement is that the components were not organized and categorized with regard to what each measure represents in the cascade of events that lead from allostasis to allostatic load. Nor was there any suggested organization in choosing original measures that would facilitate systematically relating measures to specific disease outcomes or systematically adding new measures. Allostasis and allostatic load are concepts that are mechanistically based and only as good as the information about mechanisms that lead to disease. A new way of classifying the measures must provide a handle for relating what is measured to a pathophysiological process and allow for the incorporation of new measures as more is known about underlying mechanisms leading to disease. Below we summarize a new formulation, based upon the notion of primary mediators leading to primary effects and then to secondary outcomes, which lead, finally, to tertiary outcomes that represent actual diseases.

Primary mediators - chemical messengers that are released as part of allostasis.

At present, we have four such mediators (cortisol, noradrenalin, epinephrine, DHEA). In general, the primary mediators have very widespread influences throughout the body and are very useful, when measured correctly, in predicting a variety of secondary and tertiary outcomes. Cortisol is a glucocorticoid with wide-ranging effects throughout the body. Glucocorticoid receptors are present in virtually every tissue and organ in the body and mediate effects ranging from induction of liver enzymes involved in energy metabolism to regulating trafficking of immune cells and cytokine production to facilitating formation of fear-related memories (25;30). DHEA is a functional antagonist of cortisol (20;37) which may also have effects via other signaling pathways (3); generally, low DHEA is considered deleterious, as is chronically high cortisol (29). As already noted, it is important to emphasize that the acute effects of stress mediators are generally adaptive (allostasis) and it is the chronic elevation or dysregulation of these mediators over long times that causes problems, i.e., allostatic load.

Catecholamines (adrenalin, noradrenalin) are released by the adrenal medulla and sympathetic nervous system, respectively, and they produce widespread effects throughout the body, ranging from vasoconstriction and acceleration of heart rate to trafficking of immune cells to targets, as well as enhancement of fear-related memory formation (6). Adrenergic receptors are widespread throughout the body, in blood vessels and target organs such as the liver, pancreas, as well as the brain which is not accessible to circulating catecholamines. However, catecholamines signal the brain through the sensory vagus and the nucleus of the solitary tract, as in learned fear (6).

Primary effects - cellular events, like enzymes, receptors, ion channels or structural proteins induced genomically or phosphorylated via second messenger systems, that are regulated as part of allostasis by the primary mediators.

We do not presently measure primary effects, and it may be desirable to study primary effects as the basis for the secondary and tertiary outcomes - this, in fact, is the mechanistic research that is supported by the NIH! Glucocorticoids regulate gene expression via several pathways, involving interactions with DNA via the glucocorticoid response elements (GRE's) and also via protein-protein interactions with other transcriptional regulators (28). As noted above, DHEA antagonizes glucocorticoid actions in a number of systems. Catecholamines act via alpha and beta adrenergic receptors, and beta receptors stimulate the formation of the intracellular second messenger, cyclic AMP, which, in turn, regulates intracellular events via phosphorylation, including transcription regulators via the CREB family of proteins.

In some cases, the glucocorticoid and cAMP pathways converge at the level of gene expression (e.g, see (38)). Therefore it is not surprising that secondary outcomes (see below) are the result of more than one primary mediator. Primary effects are organ and tissue specific in many cases. Hence, at this level and even more for the secondary and tertiary outcomes we must become more organ and disease specific!

Secondary outcomes - integrated processes that reflect the cumulative outcome of the primary effects in a tissue/organ specific manner in response to the primary mediators, often reflecting the actions of more than one primary mediator, including the ones described above as well as others not yet measured.

As already noted above, we measure the following secondary outcomes, which are all related to abnormal metabolism and risk for cardiovascular disease: WHR, blood pressure, glycosylated hemoglobin, cholesterol/HDL ratio, HDL cholesterol. As noted above, WHR and glycosylated hemoglobin both reflect the effects of sustained elevations in glucose and the insulin resistance that develops as a result of elevated cortisol and elevated sympathetic nervous system activity. Blood pressure elevation is part of the pathophysiologal pathway of the metabolic syndrome, but is also a more primary indication of the allostatic load that can lead to accelerated atherosclerosis as well as insulin resistance. Cholesterol and HDL cholesterol are measures of metabolic imbalance in relation to obesity and atherosclerosis and also reflect the operation of the same primary mediators as well as other metabolic hormones.

In general, in the future, we feel that we need to expand the secondary outcomes in two directions. First, there is need for more specific outcomes related to the damage pathway in cardiovascular disease and risk for MI (e.g., nitric oxide, fibrinogen). Fibrinogen has already been used as an allostatic load measure in relation to job stress and socioeconomic status (19). Second, we need outcomes related to other systems such as the brain and the immune system. For the brain, assessments of declarative and spatial memory have been employed to see individual differences in brain aging, reflecting atrophy of the hippocampus and progressive elevation of cortisol (15). For the immune system, integrated measures of the immune response such as delayed type hypersensitivity (9;10) and immunization challenge (12) should reveal the impact of allostatic load on cellular and humoral immune function and help distinguish between the immuno enhancing effects of acute stress and immunosuppressive effects of chronic stress. Moreover, assessment of the frequency and severity of the common cold (7;8) is another indirect way of assessing immune function, and this might be considered a secondary outcome.

Tertiary outcomes - these are the actual diseases or disorders which are the result of the allostatic load that is predicted from the extreme values of the secondary outcomes and of the primary mediators.

Thus far, we have utilized cardiovascular disease, decreased physical capacity and severe cognitive decline as outcomes in the successful aging studies (31;32), but some redefinition of outcomes is needed. That is, a stricter criterion based upon the new definitions of primary, secondary and tertiary outcomes would assign cognitive decline as a secondary outcome, although Alzheimer's disease or vascular dementia would be a tertiary outcomes when there is clearly a serious and permanent disease. By the same token, cancer would be a tertiary outcome, whereas the common cold would be a secondary outcome and an indirect measure, in part, of immune system efficacy, as discussed above.

This new classification of the existing measures of allostatic load should permits the following next steps:

relating progression of pathophysiology from primary mediators to secondary outcomes and then to tertiary, i.e., disease outcomes;

identifying clusters of secondary outcomes that are relevant to particular diseases;

moving to earlier ages in measuring allostatic load by relying more on secondary outcomes that are known to be risk factor for later disease; tertiary outcomes generally appear later in life, at least for dementia and cardiovascular disease, and an important question for future studies is whether secondary outcomes in younger subjects can be used as a surrogate for tertiary outcomes.

Recent Developments

The Behavioral and Social Research Program (BSR) at the National Institute on Aging sought to advance research on biopsychosocial pathways of resilience and vulnerability to late life disease through a workshop on conceptual and methodological issues surrounding the concepts of allostatic load and cumulative physiological risk more generally. They organized a 2007 workshop to bring together scientists from diverse disciplines who share an interest in understanding stress-health relationships from a life-course perspective, but who may differ in their approaches and commitment to the allostatic load model. The collaborative group focused on what is needed to advance behavioral and social research on aging within this topic area. Background materials for the meeting provide an interesting array of perspectives on allostasis and allostatic load.NIA Exploratory Workshop on Allostatic Load